A 9-month regimen of daily metformin added to insulin therapy in this patient group resulted in clinically meaningful -- but not statistically significant -- reductions in hemoglobin A1c (HbA1c) and daily insulin requirements, reported lead investigator Benjamin Nwosu, MD, of the University of Massachusetts Medical School in Worcester, and colleagues.

Glycemic control is especially hard to achieve in adolescents with type 1 diabetes, Nwosu said in an interview with MedPage Today. "The Diabetes Control and Complications Trial showed that even after carefully controlling for covariates, HbA1c was 1% higher in teens compared with adults," he said.

A chief reason for this is thought to be high levels of anti-insulin growth hormones and sex steroids, Nwosu said.

Previous metformin studies in overweight and obese children and adolescents with type 1 diabetes have yielded conflicting results, the investigators wrote. Many of these studies were extremely small, including only nine or 10 patients, and short in duration, they said.

In addition, these studies did not use a standardized insulin treatment protocol to ensure uniform glycemic control in the placebo and treatment groups, they noted.

"This is the first study to employ a standardized insulin treatment protocol, the treat-to-target insulin regimen, in the investigation of the role of adjunct metformin therapy in youth with T1D," the investigators said. This standardized regimen "ensured that all participants used the same algorithm for insulin dose adjustment throughout the duration of the study."

The study included 28 overweight or obese participants with type 1 diabetes, ages 10-20. They all went through a 3-month run-in phase with the new insulin treatment regimen. After that, they were randomized to receive either 1,000 mg metformin or placebo once-daily for 9 months.

For several study endpoints, there were small improvements that didn't reach statistical significance:

HbA1c was 0.4% lower in the treatment group than the placebo group (9.46% versus 9.85%; P=0.903).

Fasting plasma glucose was also lower in the treatment group compared with the placebo group (170.5 mg/dL versus 189.4 mg/dL; P=0.927).

The total daily dose of long-acting insulin was lower in the metformin group versus the placebo group (0.90 units/kg/day versus 1.15 units/kg/day; P=0.221).

The investigators argued that these differences were clinically meaningful but did not reach statistical significance most likely because of type 2 errors associated with the small number of participants.

"The small sample size is a major limitation and this could have limited our ability to detect significant differences in the outcome parameters," they said.

The researchers concluded that "our study suggests that prolonged treatment with adjunctive metformin could result in a clinically significant reduction in HbA1c in overweight/obese children and adolescents with T1D."

"Because of the prevalence of childhood obesity, we are seeing a change in phenotype in type 1 diabetes in young patients. This change includes increased adiposity and insulin resistance," Nwosu told MedPage Today.

"Endocrinologists have to respond to the changing phenotype of type 1 diabetes. We can't achieve HbA1c targets with insulin therapy alone. Something else might have to be added to reduce the insulin resistance in these patients," he said.

Desmond Schatz, MD, of the University of Florida in Gainesville, was much less enthusiastic about the study and much more conservative in interpreting its results.

"This is a nice study, over a long time period, with good standardization of insulin regimens, but unfortunately with a small sample size. The study is not adequately powered to report statistically significant findings," Schatz told MedPage Today via email. Schatz serves on the board of directors of the American Diabetes Association.

"Although the authors conclude that there is a difference in HbA1c between the group receiving metformin and those getting placebo, the P value of 0.903 would suggest that there really is no difference between the groups," Schatz said.

"It would have been better to conclude that there was a trend toward lower HbA1c, lower fasting glucose, and lower total daily insulin use," Schatz said. "A larger study would be needed to support the use of metformin."

This research was supported by Novo Nordisk.

Nwosu received a grant from Novo Nordisk to conduct the study, but otherwise reported no financial relationships with industry.